HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: M400284-JLR200v1 45/12/2199    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Lee, S.-J. Articles by Cooper, A. D. Search for Related Content PubMed PubMed Citation Articles by Lee, S.-J. Articles by Cooper, A. D. Social Bookmarking                      What's this?

Journal of Lipid Research, Vol. 45, 2199-2210, December 2004
Copyright © 2004 by American Society for Biochemistry and Molecular Biology

Chylomicron remnant uptake in the livers of mice expressing human apolipoproteins E3, E2 (Arg158Cys), and E3-Leiden

Sung-Joon Lee^*,, Itamar Grosskopf^*,¶,**, Sungshin Y. Choi^¶ and Allen D. Cooper^1,*,¶

^* Department of Medicine, Stanford University School of Medicine, Stanford, CA
Division of Food Sciences, College of Life and Environmental Sciences, Institute of Biomedical Science and Food Safety, Korea University, Seoul, South Korea
^¶ Research Institute, Palo Alto Medical Foundation, Palo Alto, CA
^** The Department of Medicine, Tel Aviv-Sourasky Medical Center and Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel

¹ To whom correspondence should be addressed. e-mail: adc{at}stanford.edu

Apolipoprotein E2 (apoE2) and apoE3-Leiden cause chylomicron remnant accumulation (type III hyperlipidemia). However, the degree of dyslipidemia and its penetrance are different in humans and mice. Remnant uptake by isolated liver from apoE^–/– mice transgenic for human apoE2, apoE3-Leiden, or apoE3 was measured. In the presence of both LDL receptor (LDLR) and LDL receptor-related protein (LRP), remnant uptake was apoE3>E3-Leiden>E2 mice. Absence of LDLR reduced uptake in apoE3 and apoE3-Leiden-secreting livers but not in apoE2-secreting livers. LRP inhibition with receptor-associated protein reduced uptake in apoE3- and apoE2–secreting livers, but not in apoE3-Leiden–secreting livers, regardless of the presence of LDLR. Fluorescently labeled remnants clustered with LRP in apoE3-secreting livers only in the absence of LDLR, but clustered in livers that expressed apoE2 even in the presence of LDLR, and did not cluster with LRP in livers of apoE3-Leiden even in the absence of LDLR. Remnants were reconstituted with the three human apoE isoforms. Removal by liver of mApoe^–/–/mldlr^–/– mice expressing the human LDLR was slightly greater than removal in the previous experiments with apoE3>E2> E3-Leiden.

Thus, in vivo, human apoE2 is cleared primarily by LRP, apoE3-Leiden is cleared only by the LDLR, and apoE3 is cleared by both.

Abbreviations: apoE, apolipoprotein E; DiD, 1,1'-dioctadecyl-3,3,3', 3'-tetramethylindodicarbocyanine perchlorate; HSPG, heparan sulfate proteoglycans; LRP, low density lipoprotein receptor-related protein; OG, Oregon Green; RAP, receptor-associated protein

Supplementary key words LDL receptor • LDL receptor-related protein • type III hyperlipidemia

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?